Interpretive Summary: This study extends thioredoxin (Trx)-based oxidative redox regulation to the archaea, the third domain of life. Our study suggests that Trx is nearly ubiquitous in anaerobic methanogens, enabling them to recover from oxidative stress and synchronize cellular processes, including methane biogenesis, with the availability of reductants. As methane is a valuable fuel, an end product of anaerobic biodegradation and a potent greenhouse gas, Trx may now be considered a critical participant in the global carbon cycle, climate change, and bioenergy production. Because methanogenesis developed before the oxygenation of the earth, our work raises the possibility that Trx functioned in a complex redox regulatory network in anaerobic prokaryotes at least 2.5 billion years ago.